Variable Combinations of Specific Ephrin Ligand/Eph Receptor Pairs Control Embryonic Tissue Separation

Abstract

Vertebrate embryonic cells recognize self from non-self, thus restricting repulsion at tissue boundaries, through a combination of multiple ephrins and Eph receptors, simply based on binding selectivity and asymmetric expression.

Abstract

Ephrins and Eph receptors are involved in the establishment of vertebrate tissue boundaries. The complexity of the system is puzzling, however in many instances, tissues express multiple ephrins and Ephs on both sides of the boundary, a situation that should in principle cause repulsion between cells within each tissue. Although co-expression of ephrins and Eph receptors is widespread in embryonic tissues, neurons, and cancer cells, it is still unresolved how the respective signals are integrated into a coherent output. We present a simple explanation for the confinement of repulsion to the tissue interface: Using the dorsal ectoderm–mesoderm boundary of the Xenopus embryo as a model, we identify selective functional interactions between ephrin–Eph pairs that are expressed in partial complementary patterns. The combined repulsive signals add up to be strongest across the boundary, where they reach sufficient intensity to trigger cell detachments. The process can be largely explained using a simple model based exclusively on relative ephrin and Eph concentrations and binding affinities. We generalize these findings for the ventral ectoderm–mesoderm boundary and the notochord boundary, both of which appear to function on the same principles. These results provide a paradigm for how developmental systems may integrate multiple cues to generate discrete local outcomes.

Author Summary

How embryonic tissues separate from each other to shape the developing organism is a fundamental question in developmental biology. In vertebrates, this process relies on local repulsive reactions specifically generated at contacts between cells of different types. These reactions are triggered by typical repulsive cell surface cues, the ephrin ligands, and Eph receptors. However, the expression of multiple ephrins and the Eph receptors by each cell type represents a puzzle: Why is repulsion observed only at the tissue interface and not within the tissue itself? By studying three cases of separation in the early amphibian embryo, we uncover a surprisingly simple logic underlying this phenomenon, which can be explained by the selectivity of ligand–receptor interactions and by their asymmetric distribution. The system is set such that, despite generalized interactions throughout the tissues, it is only at contacts between different cell types that the overall repulsive output is sufficiently strong to overcome cell–cell adhesion. Our study may serve as paradigm for how systematic dissection of complex cellular systems can reduce them to simple laws and make them intelligible.